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TGIF Transcription Factors Repress Acetyl Coa Metabolic Gene Expression and Promote Intestinal Tumor Growth

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TGIF Transcription Factors Repress Acetyl Coa Metabolic Gene Expression and Promote Intestinal Tumor Growth Downloaded from genesdev.cshlp.org on October 3, 2021 - Published by Cold Spring Harbor Laboratory Press TGIF transcription factors repress acetyl CoA metabolic gene expression and promote intestinal tumor growth Anant Shah,1 Tiffany A. Melhuish,1 Todd E. Fox,2 Henry F. Frierson Jr,3 and David Wotton1 1Department of Biochemistry and Molecular Genetics, Center for Cell Signaling, University of Virginia, Charlottesville, Virginia 22908, USA; 2Department of Pharmacology, 3Department of Pathology, University of Virginia, Charlottesville, Virginia 22908, USA Tgif1 (thymine–guanine-interacting factor 1) and Tgif2 repress gene expression by binding directly to DNA or in- teracting with transforming growth factor (TGF) β-responsive SMADs. Tgifs are essential for embryogenesis and may function in tumor progression. By analyzing both gain and loss of Tgif function in a well-established mouse model of intestinal cancer, we show that Tgifs promote adenoma growth in the context of mutant Apc (adenomatous pol- yposis coli). Despite the tumor-suppressive role of TGFβ signaling, transcriptome profiling of colon tumors suggests minimal effect of Tgifs on the TGFβ pathway. Instead, it appears that Tgifs, which are up-regulated in Apc mutant colon tumors, contribute to reprogramming metabolic gene expression. Integrating gene expression data from colon tumors with other gene expression and chromatin-binding data identifies a set of direct Tgif target genes encoding proteins involved in acetyl CoA and pyruvate metabolism. Analysis of both tumor and nontumor tissues indicates that these genes are targets of Tgif repression in multiple settings, suggesting that this is a core Tgif function. We propose that Tgifs play an important role in regulating basic energy metabolism in normal cells, and that this function of Tgifs is amplified in some cancers. [Keywords: TGFβ; Tgif; Wnt; cancer; colorectal cancer; gene expression; metabolism; repressor] Supplemental material is available for this article. Received August 24, 2018; revised version accepted January 24, 2019. Colorectal cancer (CRC) is among the most frequently di- sulting in phosphorylation and activation of the SMAD agnosed cancers and is the third leading cause of cancer transcription factors (Feng and Derynck 2005; Massagué deaths in adults (Miller et al. 2016). The adenomatous pol- et al. 2005). TGFβ, Activin, or Nodal signaling results pri- yposis coli (APC) gene, which is mutated in up to 80% of marily in activation of SMAD2 and SMAD3, which, in as- sporadic CRC (Kinzler and Vogelstein 1996; Segditsas and sociation with SMAD4, accumulate in the nucleus to Tomlinson 2006), encodes a scaffold-like protein that as- activate gene expression. TGFβ signaling is tumor suppres- sembles a complex of proteins including β-catenin, Axins, sive in many cancers, in part due to the antiproliferative ef- and GSK3β (Sancho et al. 2004; Clevers and Nusse 2012). fects of the pathway (Levy and Hill 2006; Massagué 2008). In the absence of Wnt ligands, β-catenin is phosphorylated Inactivating mutations in the TGFBR2 gene, encoding the and degraded. Wnt signaling prevents phosphorylation type II receptor, are found in around 25% of CRC (Marko- and destruction of β-catenin, allowing it to accumulate witz et al. 1995; Grady et al. 1999). Loss of heterozygosity and activate gene expression. Mutation or deletion of of a region of chromosome 18 that includes both SMAD2 APC results in constitutive β-catenin-dependent gene ac- and SMAD4 is seen in almost 70% of CRC but is less fre- tivation, primarily via interactions with the TCF/LEF quently observed in colorectal adenomas (Vogelstein transcription factors (Polakis 1995; Sancho et al. 2004). et al. 1988). Conditional inactivation of the mouse Tgfbr2 Inactivation of one allele of the mouse Apc gene by gene in combination with an Apc mutation results in pro- germ-line mutation (Moser et al. 1990; Fodde et al. 1994; gression to invasive adenocarcinoma, whereas homozy- Oshima et al. 1995) or by CRE-mediated excision of a gous Tgfbr2 deletion alone in the intestine has no effect loxP-flanked exon (Shibata et al. 1997; Colnot et al. (Muñoz et al. 2006). 2004; Hinoi et al. 2007) causes multiple adenomas, due TGIF1 (thymine–guanine-interacting factor) and the to sporadic inactivation of the remaining allele. closely related TGIF2 are homeodomain transcription In response to transforming growth factor β (TGFβ) li- gands, the type I and type II receptors form a complex, re- © 2019 Shah et al. This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publi- cation date (see http://genesdev.cshlp.org/site/misc/terms.xhtml). After Corresponding author: [email protected] six months, it is available under a Creative Commons License (Attribu- Article published online ahead of print. Article and publication date are tion-NonCommercial 4.0 International), as described at http://creative- online at http://www.genesdev.org/cgi/doi/10.1101/gad.320127.118. commons.org/licenses/by-nc/4.0/. GENES & DEVELOPMENT 33:1–15 Published by Cold Spring Harbor Laboratory Press; ISSN 0890-9369/19; www.genesdev.org 1 Downloaded from genesdev.cshlp.org on October 3, 2021 - Published by Cold Spring Harbor Laboratory Press Shah et al. factors that are members of the TALE (three-amino-acid Wnt/β-catenin pathway, although this appeared to be in- loop extension) superfamily (Bertolino et al. 1995; Melhu- dependent of effects on Axins (Wang et al. 2017). Thus, ish et al. 2001; Hyman et al. 2003). Other TALE homeodo- Tgifs can promote tumorigenesis, but questions regarding main proteins include the Meis and Pbx families that mechanisms of action and potential overlapping roles of activate gene expression (Bürglin and Affolter 2016). In Tgif1 and Tgif2 remain. contrast, TGIF1 and TGIF2 are transcriptional repressors We used genetically engineered mouse models to that interact with multiple general corepressors, includ- address the function of Tgifs in intestinal epithelial neo- ing mSin3 and histone deacetylases (Wotton et al. plasms and to identify downstream Tgif target genes. 1999a; Melhuish et al. 2001). In addition, TGIF1 recruits Overexpression of TGIF1 in intestinal epithelial cells in- CtBP1/2 corepressors via a conserved interaction motif creased the size and number of adenomas in the small in- (Melhuish and Wotton 2000). Tgifs limit the response to testine, and deletion of Tgif1 and Tgif2 reduced tumor size TGFβ signaling by recruiting corepressors to the SMAD in both the small intestine and colon. Transcriptional pro- transcription factors (Wotton et al. 1999a; Melhuish filing of colon tumors from these mice revealed little ef- et al. 2001). In addition to SMAD interaction, other mech- fect of Tgifs on either Wnt/β-catenin or TGFβ signaling. anisms for TGFβ pathway inhibition have been suggested, Instead, we found that deleting Tgifs from colon tumors including promoting SMAD2 ubiquitylation and degrada- caused changes in expression of genes affecting multiple tion or preventing SMAD2 phosphorylation in response to metabolic pathways. Integrating these data with addition- TGFβ signaling (Seo et al. 2004, 2006). Loss-of-function al gene expression profiling results suggests that Tgifs play TGIF1 mutations are associated with holoprosencephaly a fundamental role in regulating energy metabolism, and (HPE), a severe genetic disease affecting forebrain develop- may contribute to the reprogramming of metabolic gene ment (Wotton and Taniguchi 2018). Mouse models of expression that occurs in CRC. Tgif1 and Tgif2 loss of function suggest they play a redun- dant, but essential role in early embryogenesis (Powers et al. 2010). Conditional mutants survive to mid-gestation Results with multiple developmental abnormalities, including Increased Tgif expression in colorectal tumors HPE (Taniguchi et al. 2012, 2017). Although developmental defects in embryos lacking Analysis of TCGA colorectal data showed elevated TGIF1 Tgif1 and Tgif2 can be partly rescued by reducing TGFβ and TGIF2 in adenocarcinomas (Fig. 1A). Similar results family signaling through mutation of Nodal (Powers were seen with additional CRC data sets, and in compari- et al. 2010; Taniguchi et al. 2012, 2017), transcriptome son of paired tumor and normal samples, TGIF1 expres- profiling of early embryos or primary mouse embryo fi- sion was higher in tumors in all cases (Supplemental Fig. broblasts (MEFs) lacking Tgifs suggests that the majority S1). Mouse models of intestinal cancer, based on genetic of gene expression changes are unlikely to be due to al- alterations found in human cancers or treatment with tered TGFβ family signaling (Zerlanko et al. 2012; Ander- chemical carcinogens, have been analyzed by gene expres- son et al. 2017). TGIF1 was first identified by its ability to sion array (Kaiser et al. 2007). In these analyses, Tgif1 ex- bind a retinoid response element of the Rbp2 gene and re- pression was significantly higher in the azoxymethane duce activation by RXR nuclear receptors (Bertolino et al. (AOM) and Apc mutant models but not in one based on in- 1995). TGIFs can bind directly to DNA and repress tran- activation of Smad3, a component of the TGFβ signaling scription via a well-defined consensus site, cTGTCAa, pathway (Supplemental Fig. S2A). Similar results were where the central five bases are most important (Berto- found with Tgif2 expression in this data set, although the lino et al. 1995; Wotton et al. 1999b). Direct repression signal in the AOM samples was too variable to reach stat- via this consensus site has been shown for a small num- istical significance. ber of Tgif target genes (Anderson et al. 2017; Taniguchi To test expression of Tgifs in Apc mutant mouse colon et al. 2017). Recent genome-wide analysis identified a tumors, we combined a Villin-Cre transgene with a loxP- large number of potential Tgif1-binding sites, with en- flanked allele of Apc isolated normal colon and colon tu- richment for the known TGIF consensus element (Lee mors at 12 wk of age and analyzed gene expression by et al.
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